The gene that causes a form of leukemia also appears to spawn mutations in itself, leading to drug-resistant disease, according to City of Hope researchers. The finding provides a new tool for understanding how resistant disease develops and could lead to methods to overcome it.
Reporting in the Feb. 12 issue of The Journal of Biological Chemistry, WenYong Chen, Ph.D., assistant professor of biology, and a team of researchers sought to understand how mutations in a gene called BCR-ABL make chronic myelogenous leukemia, or CML, resistant to drugs such as imatinib.
 WenYong Chen (Photo by Darrin S. Joy) |
BCR-ABL is an abnormal gene formed when genes from two different chromosomes mistakenly join together in a bone marrow cell. The abnormal gene makes a new “fusion protein” that spins white blood cells out of control and causes CML.
Imatinib, also known as Gleevec, revolutionized CML treatment by allowing patients to control their disease with a daily pill. The drug disables the BCR-ABL protein, which the BCR-ABL gene makes.
Over time, though, the BCR-ABL gene changes and mutates, which alters the protein so that imatinib no longer recognizes it. That leads to disease that resists imatinib.
City of Hope researchers wanted to follow cells’ path to drug resistance. They grew CML cells in the presence of imatinib in the lab and carefully tracked cells’ growth pattern as they became drug resistant and flourished.
The pattern showed that the cells suddenly developed new mutations in the BCR-ABL gene. Surprisingly, though, when researchers completely turned the BCR-ABL gene off before adding imatinib to the cells, the BCR-ABL gene did not mutate. They found the BCR-ABL gene was more prone to mutate when it was on its native chromosome than on other chromosomes.
That means that BCR-ABL’s gene activity actually causes it to mutate.
“We knew from previous research that BCR-ABL was involved with its own mutation, but we didn’t realize its gene activity was required,” said Chen. The finding suggests that BCR-ABL activity is the driving force that makes CML cells genetically unstable and prone to mutation.
Further studies by the team will aim to uncover more details about the underlying processes leading to CML drug resistance with the aim of boosting treatment with Gleevec and similar drugs.
Additional authors on the study include Hongfeng Yuan, Ph.D., Zhiqiang Wang, Ph.D., Chunggang Gao, Wengang Chen, Ph.D., Qin Huang, M.D., Ph.D., Jiing-Kuan Yee, Ph.D., and Ravi Bhatia, M.D.
Grants from the U.S. Department of Defense, STOP CANCER and the V Foundation for Cancer Research supported the work.
Chronic myelogenous leukemia: Two chromosomes gone awry One accidental swap of parts of two chromosomes can make a big difference to human health. When genetic material from chromosome 9 mistakenly switches places with material from chromosome 22, it results, in part, in a shortened chromosome 22 (called the Philadelphia chromosome). The Philadelphia chromosome contains the abnormal fusion gene BCR-ABL, formed by a combination of material from chromosomes 9 and 22. BCR-ABL encodes an enzyme — a type of tyrosine kinase — that is uncontrolled and leads to cancer. Researchers have found that the Philadelphia chromosome is not only found in most instances of chronic myelogenous leukemia, but also in some cases of acute lymphoblastic leukemia. |
